Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and the 8th most common cancer occurring in men in the US. Treatment of early stage disease is efficacious, but results in significant reduction in quality of life. Screening for HNSCC is not routine and patients often present with late stage or metastatic disease. Median survival for patients with late stage, recurrent or metastatic HNSCC is less than one year. Thus there is a clear unmet need in the treatment of HNSCC. Single site studies have shown that photodynamic therapy (PDT) of both early and late stage HNSCC results in excellent outcome with good retention of function. In spite of these studies PDT remains an underutilized niche therapy due to the lack of studies demonstrating that PDT is comparable to conventional therapy in treatment outcome and results in fewer treatment associated morbidities. The overall hypothesis of this program project grant is that PDT is an effective therapy for HNSCC, which will result in long-term tumor responses that compare to the current treatment modalities, but will result in significantly fewer quality of life issues. The ovrall goal of the current application is to move PDT from a niche therapy to the standard of care (SoC) for HNSCC, thus providing a novel treatment option for HNSCC with lower associated morbidities than the current SoC for this malignancy. To accomplish this goal a tightly focused program consisting of three projects is proposed. Three clinical trials are proposed in Project 1: two multi-center randomized Phase II trials examining the effectiveness of PDT against the SoC for early stage and advanced recurrent disease and a Phase I trial examining the safety of PDT-generated vaccines as an adjuvant to surgical treatment of HNSCC. The research projects are designed to enhance the efficacy of PDT in the treatment of HNSCC. Incomplete tumor response to PDT can be due to inadequate photosensitizer retention. In Project 2 HNSCC targeted photosensitizers with better tumor retention properties will be selected and tested. HNSCC patients frequently exhibit suppressed immune responses; PDT enhances anti-tumor immunity. The ability of PDT or vaccination with PDT generated tumor cell lysates to convert the HNSCC induced immunosuppressive microenvironment to an immune stimulatory environment in patients and murine model systems will be tested in Project 3; this project will also continue t determine the mechanisms behind PDT enhancement of anti-tumor immunity. The Projects will be supported by 4 cores, including Bioanalysis and Optics Cores. The Bioanalysis core will test previously identified predictors of the clinical response to PDT. The Optics Core will analyze dosimetry and provide tissue and blood optical measurements that will be correlated to the clinical response. This PPG is compelling in that the highly integrated proposed studies have a strong potential of demonstrating the effectiveness of PDT as a treatment modality for HNSCC that preserves patient quality of life while simultaneously exploring novel mechanisms to enhance treatment outcomes beyond those currently seen with SoC modalities.